Diseases of the prostate, including benign prostatic hyperplasia, prostatic cancer, and prostatitis may be related to hyperandrogenic stimulation caused by an excessive accumulation of testosterone ("T") or similar androgenic hormones in the metabolic system. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethyl-isobutyranilide. See Neri, et al., Endocrinol. 1972, 91 (2). However, these products, though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host and/or initiate feed-back effects which would cause hyperstimulation of the testes.
The principal mediator of androgenic activity in the prostate is 5.alpha.-dihydrotestosterone ("DHT"), formed locally in the prostate by the action of testosterone-5.alpha.-reductase (or simply 5.alpha.-reductase). Inhibitors of 5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in the prostate. See especially U.S. Pat. No. 4,377,584, issued Mar. 22, 1983, and U.S. Pat. No. 4,760,071, issued Jul. 26, 1988, both assigned to Merck & Co., Inc.
The enzyme 5.alpha.-reductase catalyzes the reduction of testosterone to the more potent androgen, dihydrotestosterone, as shown below: ##STR1##
Finasteride, (17.beta.-(N-tert-butylcarbamoyl)-3-oxo-4-aza-5.alpha.-androst-1-ene-3-one ) as shown below, is a potent inhibitor of the human prostate enzyme. ##STR2##
Under the trade name PROSCAR.RTM., finasteride is known to be useful in the treatment of hyperandrogenic conditions; see eg. U.S. Pat. No. 4,760,071. Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition afflicting to some degree the majority of men over age 55. Under the trade name PROPECIA.RTM., a lower dose of fmasteride is prescribed for the treatment of male pattern hair loss. Finasteride's utility in the treatment of androgenic alopecia and prostatic carcinoma is also disclosed in the following documents: EP 0 285,382, published Oct. 5, 1988; EP 0 285,383, published Oct. 5, 1988.
There are two isozymes of 5.alpha.-reductase in humans. One isozyme (type 1 or 5.alpha.-reductase 1) predominates in sebaceous glands of facial and skin tissue and is relatively insensitive to finasteride (see, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (November 1992)); the other (type 2 or 5.alpha.-reductase 2) predominates in the prostate and is potently inhibited by finasteride. A genus of 16.beta.-substituted-4-azasteroids are described in U.S. Pat. No. 5,719,158.
Calcium channel blockers such as nifedipine, verapamil and diltiazem, are used in the treatment of cardiovascular diseases. Calcium channel blockers or antagonists are compounds which delay or prevent the cardiac contracture which is believed to be caused by an accumulation of intracellular calcium under ischemic conditions. Calcium overload, during ischemia, can have a number of additional adverse effects which would further compromise the ischemic myocardium. These include less efficient use of oxygen for ATP production, activation of mitochondrial fatty acid oxidation, and possibly, promotion of cell necrosis. Thus, calcium channel blockers are useful in the treatment or prevention of cardiac conditions, such as angina pectoris, cardiac arrhythmias, heart attacks and cardiac hypertropy. Calcium channel blockers also possess vasodilator activity and are thus useful as antihypertensives and for the treatment of coronary vasospasm. Calcium channel blockers of the verapamil type are known to lower elevated intraocular pressure. See U.S. Pat. No. 4,981,871. Calcium channel blockers are not suggested as useful for treating androgen-related conditions, including benign prostatic hyperplasia.